Brain-derived neurotrophic factor (BDNF) is required to maintain the integrity of dopamine neurons in the substantia nigra and their medium spiny neuron postsynaptic targets in the striatum. The general hypothesis of this proposal is that the TrkB and D1 receptors on postsynaptic medium spiny neurons interact to induce a CREB-driven response of target genes that may contribute to the neuroplastic changes associated with exposure to psychostimulants. Our preliminary data indicate that genetic depletion of BDNF decreases expression of the opioid peptides in striatal mediums spiny neurons. We propose that activation of the Erk/MAPK-CREB pathway downstream of the TrkB receptor is the underlying mechanism by which BDNF regulates striatal gene expression of opioid peptides and that intrastriatal. infusion of BDNF will restore opioid peptide expression. Finally, we will administer amphetamine to BDNF-deficient mice to begin to investigate how BDNF and psychostimulants interact to regulate gene and phospho-protein expression in striatal medium spiny neurons. [unreadable] [unreadable] [unreadable]